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Lars H. Vorland - One of the best experts on this subject based on the ideXlab platform.
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staphylococcus aureus small colony variants are resistant to the antimicrobial peptide Lactoferricin b
Journal of Antimicrobial Chemotherapy, 2005Co-Authors: Orjan Samuelsen, Hanne H. Haukland, Hilde Ulvatne, Kjersti Sandvik, Barbara C Kahl, Christof Von Eiff, Richard A Proctor, Lars H. VorlandAbstract:Objectives To determine whether Staphylococcus aureus small colony variants (SCVs) are resistant to the antimicrobial peptide Lactoferricin B. To assess if deficiency in transmembrane potential, a common characteristic of SCVs that are haemin- or menadione-auxotrophs, affects the uptake of the peptide into the bacterial cytoplasm. Methods A broth microdilution technique was used for susceptibility testing to determine the MIC of Lactoferricin B for SCVs with three different auxotrophisms (haemin, menadione or thymidine) and their isogenic parent strains. Both clinical isolates and genetically defined mutants were used. The internalization of Lactoferricin B in a hemB mutant and the respective parent strain was studied using transmission electron microscopy and immunogold labelling. Results All SCVs showed reduced susceptibility to Lactoferricin B irrespective of their auxotrophy compared with their isogenic parent strains. The MIC for all SCVs was >256 mg/L, whereas the MICs for the parent strains ranged from 16-256 mg/L. Surprisingly, the hemB mutant contained significantly more Lactoferricin B intracellularly than the respective parent strain. Conclusions The resistance mechanism of SCVs towards the antimicrobial peptide Lactoferricin B is presumably caused by the metabolic changes present in SCVs rather than by a changed transmembrane potential of SCVs or reduced uptake of the peptide.
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induced resistance to the antimicrobial peptide Lactoferricin b in staphylococcus aureus
FEBS Letters, 2005Co-Authors: Håvard Jenssen, Hanne H. Haukland, Hilde Ulvatne, Kjersti Sandvik, Lars H. Vorland, Orjan Samuelsen, Manuela KramerAbstract:This study was designed to investigate inducible intrinsic resistance against Lactoferricin B in Staphylococcus aureus. Serial passage of seven S. aureus strains in medium with increasing concentrations of peptide resulted in an induced resistance at various levels in all strains. The induced resistance was unstable and decreased relatively rapidly during passages in peptide free medium but the minimum inhibitory concentration remained elevated after thirty passages. Cross-resistance to penicillin G and low-level cross-resistance to the antimicrobial peptides indolicidin and Ala3,13,18-magainin was observed. No cross-resistance was observed to the human cathelicidin LL-37. In conclusion, this study shows that S. aureus has intrinsic resistance mechanisms against antimicrobial peptides that can be induced upon exposure, and that this may confer low-level cross-resistance to other antimicrobial peptides.
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Lactoferricin b inhibits bacterial macromolecular synthesis in escherichia coli and bacillus subtilis
Fems Microbiology Letters, 2004Co-Authors: Hilde Ulvatne, Hanne H. Haukland, Lars H. Vorland, Orjan Samuelsen, Manuela KramerAbstract:Most antimicrobial peptides have an amphipathic, cationic structure, and an effect on the cytoplasmic membrane of susceptible bacteria has been postulated as the main mode of action. Other mechanisms have been reported, including inhibition of cellular functions by binding to DNA, RNA and proteins, and the inhibition of DNA and/or protein synthesis. Lactoferricin B (Lfcin B), a cationic peptide derived from bovine lactoferrin, exerts slow inhibitory and bactericidal activity and does not lyse susceptible bacteria, indicating a possible intracellular target. In the present study incorporation of radioactive precursors into DNA, RNA and proteins was used to demonstrate effects of Lfcin B on macromolecular synthesis in bacteria. In Escherichia coli UC 6782, Lfcin B induces an initial increase in protein and RNA synthesis and a decrease in DNA synthesis. After 10 min, the DNA-synthesis increases while protein and RNA-synthesis decreases significantly. In Bacillus subtilis, however, all synthesis of macromolecules is inhibited for at least 20 min. After 20 min RNA-synthesis increases. The results presented here show that Lfcin B at concentrations not sufficient to kill bacterial cells inhibits incorporation of radioactive precursors into macromolecules in both Gram-positive and Gram-negative bacteria.
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proteases in escherichia coli and staphylococcus aureus confer reduced susceptibility to Lactoferricin b
Journal of Antimicrobial Chemotherapy, 2002Co-Authors: Hilde Ulvatne, Hanne H. Haukland, Orjan Samuelsen, Manuela Kramer, Lars H. VorlandAbstract:Lactoferricin B is a cationic antimicrobial peptide derived from the N-terminal part of bovine lactoferrin. The effect of bacterial proteases on the antibacterial activity of Lactoferricin B towards Escherichia coli and Staphylococcus aureus was investigated using various protease inhibitors and protease-deficient E. coli mutants. Sodium-EDTA, a metalloprotease inhibitor, was the most efficient inhibitors in both species, but combinations of sodium-EDTA with other types of protease inhibitor gave a synergic effect. The results indicate that several groups of proteases are involved in resistance to Lactoferricin B in both E. coli and S. aureus. We also report that genetic inactivation of the heat shock-induced serine protease DegP increased the susceptibility to Lactoferricin B in E. coli, suggesting that this protease, at least, is involved in reduced susceptibility to Lactoferricin B.
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evidence for a direct antitumor mechanism of action of bovine Lactoferricin
Anticancer Research, 2002Co-Authors: Liv Tone Eliassen, Lars H. Vorland, John S Svendsen, Gerd Berge, Baldur Sveinbjornsson, Oystein RekdalAbstract:Background Bovine lactoferrin (LFB) and its pepsin-generated peptide Lactoferricin (LfcinB) possess antitumor activities. The mechanism underlying the antitumor activities of LfcinB in vivo has not been elucidated. In this study the antitumor activities exerted by LFB, LfcinB and murine Lactoferricin (LfcinM) on murine tumor cell lines and experimental tumors were investigated. MATEIALS AND METHODS: The protein and peptides were tested against Meth A fibrosarcoma, B16F10 melanoma and C26 colon carcinoma cells in vitro and their derived tumors in vivo, exploring the mechanisms of antitumor activity by way of histological and scanning electron microscopical studies. Results LfcinB exerted significant cytotoxic activity against the three tumor cell lines in vitro and significantly reduced the size of solid Meth A tumors. Scanning electron micrographs revealed tumor cell membrane disruption and eventually cell lysis, while extensive hemorrhagic necrosis was apparent in tumor sections one day after LfcinB treatment. No species-specific antitumor effect of LfcinM was observed. Conclusion Our study demonstrated that LfcinB elicits an antitumor effect mediated through a direct mechanism of action not observed with LFB or LfcinM.
Hans J Vogel - One of the best experts on this subject based on the ideXlab platform.
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anticancer activities of bovine and human Lactoferricin derived peptides
Biochemistry and Cell Biology, 2017Co-Authors: Mauricio Arias, Robert E. W. Hancock, Hans J Vogel, Jan G M Bolscher, Evan F Haney, Ashley L Hilchie, Eric M HyndmanAbstract:Lactoferrin (LF) is a mammalian host defense glycoprotein with diverse biological activities. Peptides derived from the cationic region of LF possess cytotoxic activity against cancer cells in vitro and in vivo. Bovine Lactoferricin (LFcinB), a peptide derived from bovine LF (bLF), exhibits broad-spectrum anticancer activity, while a similar peptide derived from human LF (hLF) is not as active. In this work, several peptides derived from the N-terminal regions of bLF and hLF were studied for their anticancer activities against leukemia and breast-cancer cells, as well as normal peripheral blood mononuclear cells. The cyclized LFcinB-CLICK peptide, which possesses a stable triazole linkage, showed improved anticancer activity, while short peptides hLF11 and bLF10 were not cytotoxic to cancer cells. Interestingly, hLF11 can act as a cell-penetrating peptide; when combined with the antimicrobial core sequence of LFcinB (RRWQWR) through either a Pro or Gly-Gly linker, toxicity to Jurkat cells increased. Together, our work extends the library of LF-derived peptides tested for anticancer activity, and identified new chimeric peptides with high cytotoxicity towards cancerous cells. Additionally, these results support the notion that short cell-penetrating peptides and antimicrobial peptides can be combined to create new adducts with increased potency.
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bovine and human Lactoferricin peptides chimeras and new cyclic analogs
Biometals, 2014Co-Authors: Mauricio Arias, Kamran Nazmi, Jan G M Bolscher, Evan F Haney, Lindsey J Mcdonald, Hans J VogelAbstract:Lactoferrin (LF) is an important antimicrobial and immune regulatory protein present in neutrophils and most exocrine secretions of mammals. The antimicrobial activity of LF has been related to the presence of an antimicrobial peptide sequence, called Lactoferricin (LFcin), located in the N-terminal region of the protein. The antimicrobial activity of bovine LFcin is considerably stronger than the human version. In this work, chimera peptides combining segments of bovine and human LFcin were generated in order to study their antimicrobial activity and mechanism of action. In addition, the relevance of the conserved disulfide bridge and the resulting cyclic structure of both LFcins were analyzed by using "click chemistry" and sortase A-catalyzed cyclization of the peptides. The N-terminal region of bovine LFcin (residues 17-25 of bovine LF) proved to be very important for the antimicrobial activity of the chimera peptides against E. coli, when combined with the C-terminal region of human LFcin. Similarly the cyclic bovine LFcin analogs generated by "click chemistry" and sortase A preserved the antimicrobial activity of the original peptide, showing the significance of these two techniques in the design of cyclic antimicrobial peptides. The mechanism of action of bovine LFcin and its active derived peptides was strongly correlated with membrane leakage in E. coli and up to some extent with the ability to induce vesicle aggregation. This mechanism was also preserved under conditions of high ionic strength (150 mM NaCl) illustrating the importance of these peptides in a more physiologically relevant system.
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structural and biophysical characterization of an antimicrobial peptide chimera comprised of Lactoferricin and lactoferrampin
Biochimica et Biophysica Acta, 2012Co-Authors: Evan F Haney, Jan G M Bolscher, Kamran Nazmi, Hans J VogelAbstract:Lactoferricin and lactoferrampin are two antimicrobial peptides found in the N-terminal lobe of bovine lactoferrin with broad spectrum antimicrobial activity against a range of Gram-positive and Gram-negative bacteria as well as Candida albicans. A heterodimer comprised of lactoferrampin joined to a fragment of Lactoferricin was recently reported in which these two peptides were joined at their C-termini through the two amino groups of a single Lys residue (Bolscher et al., 2009, Biochimie 91(1):123-132). This hybrid peptide, termed LFchimera, has significantly higher antimicrobial activity compared to the individual peptides or an equimolar mixture of the two. In this work, the underlying mechanism behind the increased antibacterial activity of LFchimera was investigated. Differential scanning calorimetry studies demonstrated that all the peptides influenced the thermotropic phase behaviour of anionic phospholipid suspensions. Calcein leakage and vesicle fusion experiments with anionic liposomes revealed that LFchimera had enhanced membrane perturbing properties compared to the individual peptides. Peptide structures were evaluated using circular dichroism and NMR spectroscopy to gain insight into the structural features of LFchimera that contribute to the increased antimicrobial activity. The NMR solution structure, determined in a miscible co-solvent mixture of chloroform, methanol and water, revealed that the Lys linkage increased the helical content in LFchimera compared to the individual peptides, but it did not fix the relative orientations of Lactoferricin and lactoferrampin with respect to each other. The structure of LFchimera provides insight into the conformation of this peptide in a membranous environment and improves our understanding of its antimicrobial mechanism of action.
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serum stabilities of short tryptophan and arginine rich antimicrobial peptide analogs
PLOS ONE, 2010Co-Authors: Leonard T Nguyen, Johnny K Chau, Nicole A Perry, Leonie De Boer, Sebastian A J Zaat, Hans J VogelAbstract:Background: Several short antimicrobial peptides that are rich in tryptophan and arginine residues were designed with a series of simple modifications such as end capping and cyclization. The two sets of hexapeptides are based on the Trp- and Arg-rich primary sequences from the "antimicrobial centre" of bovine Lactoferricin as well as an antimicrobial sequence obtained through the screening of a hexapeptide combinatorial library. Methodology/Principal Findings: HPLC, mass spectrometry and antimicrobial assays were carried out to explore the consequences of the modifications on the serum stability and microbicidal activity of the peptides. The results show that C-terminal amidation increases the antimicrobial activity but that it makes little difference to its proteolytic degradation in human serum. On the other hand, N-terminal acetylation decreases the peptide activities but significantly increases their protease resistance. Peptide cyclization of the hexameric peptides was found to be highly effective for both serum stability and antimicrobial activity. However the two cyclization strategies employed have different effects, with disulfide cyclization resulting in more active peptides while backbone cyclization results in more proteolytically stable peptides. However, the benefit of backbone cyclization did not extend to longer 11-mer peptides derived from the same region of Lactoferricin. Mass spectrometry data support the serum stability assay results and allowed us to determine preferred proteolysis sites in the peptides. Furthermore, isothermal titration calorimetry experiments showed that the peptides all had weak interactions with albumin, the most abundant protein in human serum. Conclusions/Significance: Taken together, the results provide insight into the behavior of the peptides in human serum and will therefore aid in advancing antimicrobial peptide design towards systemic applications
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human Lactoferricin is partially folded in aqueous solution and is better stabilized in a membrane mimetic solvent
Antimicrobial Agents and Chemotherapy, 2005Co-Authors: Howard N Hunter, Håvard Jenssen, Tore Jarl Gutteberg, Ross A Demcoe, Hans J VogelAbstract:Lactoferricins are highly basic bioactive peptides that are released in the stomach through proteolytic cleavage of various lactoferrin proteins. Here we have determined the solution structure of human Lactoferricin (LfcinH) by conventional two-dimensional nuclear magnetic resonance methods in both aqueous solution and a membrane mimetic solvent. Unlike the 25-residue bovine Lactoferricin (LfcinB), which adopts a somewhat distorted antiparallel β sheet, the longer LfcinH peptide shows a helical content from Gln14 to Lys29 in the membrane mimetic solvent but a nonexistent β-sheet character in either the N- or C-terminal regions of the peptide. The helical characteristic of the LfcinH peptide resembles the conformation that this region adopts in the crystal structure of the intact protein. The LfcinH structure determined in aqueous solution displays a nascent helix in the form of a coiled conformation in the region from Gln14 to Lys29. Numerous hydrophobic interactions create the basis for the better-defined overall structure observed in the membrane mimetic solvent. The 49-residue LfcinH peptide isolated for these studies was found to be slightly longer than previously reported peptide preparations and was found to have an intact peptide bond between residues Ala11 and Val12. The distinct solution structures of LfcinH and LfcinB represent a novel difference in the physical properties of these two peptides, which contributes to their unique physiological activities.
John S Svendsen - One of the best experts on this subject based on the ideXlab platform.
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in vitro characterization of human peptide transporter hpept1 interactions and passive permeation studies of short cationic antimicrobial peptides
Journal of Medicinal Chemistry, 2011Co-Authors: Goril Eide Flaten, John S Svendsen, Gabor Kottra, Wenche Stensen, Geir Villy Isaksen, Rasmus Karstad, Hannelore Daniel, Johan SvensonAbstract:The present study assesses the permeation of cationic antimicrobial di- and tripeptides derived from Lactoferricin via interaction with the human intestinal peptide transporter hPEPT1 and via passi...
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in vitro characterization of human peptide transporter hpept1 interactions and passive permeation studies of short cationic antimicrobial peptides
Journal of Medicinal Chemistry, 2011Co-Authors: Goril Eide Flaten, John S Svendsen, Gabor Kottra, Wenche Stensen, Geir Villy Isaksen, Rasmus Karstad, Hannelore Daniel, Johan SvensonAbstract:The present study assesses the permeation of cationic antimicrobial di- and tripeptides derived from Lactoferricin via interaction with the human intestinal peptide transporter hPEPT1 and via passive routes. While some tested peptides displayed moderate affinity (0.6 and 2.7 mM) for interaction with hPEPT1, none served as substrate for hPEPT1 expressed by Xenopus laevis oocytes. It is shown that structural strategies employed to generate sufficient biological activity and metabolic stability such as introduction of large hydrophobic unnatural amino acids and different C-terminal modifications counteracted hPEPT1 mediated uptake. Most of the included peptides were nevertheless shown to permeate at rates suggesting moderate to excellent human oral absorption in the applied phospholipid vesicle-based passive permeation assay. Although the main factor governing passive permeation appears to be the hydrophobicity, peptide structure was also important and the overall permeation behavior was difficult to predict. Comparisons with a theoretical prediction model were also performed.
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the medicinal chemistry of short Lactoferricin based antibacterial peptides
Current Medicinal Chemistry, 2007Co-Authors: Bengt Erik Haug, Morten B Strom, John S SvendsenAbstract:This review discusses antibacterial peptides from the perspective of development into clinically useful chemotherapeutic drugs using short Lactoferricin based peptides as examples. The review shows how important features for antibacterial activity can be identified and explored using the molecular properties of a range of natural and non-natural amino acids. The results have been further refined quantitatively using a "soft-modelling" approach where important structural parameters that influence the antibacterial activity of 15-residue model peptides were identified. The review describes how this knowledge is utilised to generate pharmacophores for antibacterial efficacy. These pharmacophores turn out to be surprisingly small and relatively consistent between typical Gram-negative and Gram-positive bacteria leading to the discovery of a novel class of short synthetic cationic antimicrobial peptides. These compounds are found to have high antibacterial activity against several bacterial strains that are resistant to commercial antibiotics, and are promising as future clinical candidates for treatment of infections caused by several clinically relevant pathogens.
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evidence for a direct antitumor mechanism of action of bovine Lactoferricin
Anticancer Research, 2002Co-Authors: Liv Tone Eliassen, Lars H. Vorland, John S Svendsen, Gerd Berge, Baldur Sveinbjornsson, Oystein RekdalAbstract:Background Bovine lactoferrin (LFB) and its pepsin-generated peptide Lactoferricin (LfcinB) possess antitumor activities. The mechanism underlying the antitumor activities of LfcinB in vivo has not been elucidated. In this study the antitumor activities exerted by LFB, LfcinB and murine Lactoferricin (LfcinM) on murine tumor cell lines and experimental tumors were investigated. MATEIALS AND METHODS: The protein and peptides were tested against Meth A fibrosarcoma, B16F10 melanoma and C26 colon carcinoma cells in vitro and their derived tumors in vivo, exploring the mechanisms of antitumor activity by way of histological and scanning electron microscopical studies. Results LfcinB exerted significant cytotoxic activity against the three tumor cell lines in vitro and significantly reduced the size of solid Meth A tumors. Scanning electron micrographs revealed tumor cell membrane disruption and eventually cell lysis, while extensive hemorrhagic necrosis was apparent in tumor sections one day after LfcinB treatment. No species-specific antitumor effect of LfcinM was observed. Conclusion Our study demonstrated that LfcinB elicits an antitumor effect mediated through a direct mechanism of action not observed with LFB or LfcinM.
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simple parameterization of non proteinogenic amino acids for qsar of antibacterial peptides
Journal of Peptide Science, 2002Co-Authors: Tore Lejon, John S Svendsen, Bengt Erik HaugAbstract:The antibacterial activity of bovine Lactoferricin-(17-31)-pentadecapeptide against Escherichia coli and Staphylococcus aureus is sensitive to substitution of the Trp residues, and synthetic peptides with phenylalanine and any of eight non-proteinogenic aromatic amino acids greatly affected antibiotic activity. Using simple size-related descriptors for the new amino acids it is possible to develop quantitative structure-activity relationships (QSARs) that can be used as tools in the search for more active peptides.
Johan Svenson - One of the best experts on this subject based on the ideXlab platform.
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in vitro characterization of human peptide transporter hpept1 interactions and passive permeation studies of short cationic antimicrobial peptides
Journal of Medicinal Chemistry, 2011Co-Authors: Goril Eide Flaten, John S Svendsen, Gabor Kottra, Wenche Stensen, Geir Villy Isaksen, Rasmus Karstad, Hannelore Daniel, Johan SvensonAbstract:The present study assesses the permeation of cationic antimicrobial di- and tripeptides derived from Lactoferricin via interaction with the human intestinal peptide transporter hPEPT1 and via passi...
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in vitro characterization of human peptide transporter hpept1 interactions and passive permeation studies of short cationic antimicrobial peptides
Journal of Medicinal Chemistry, 2011Co-Authors: Goril Eide Flaten, John S Svendsen, Gabor Kottra, Wenche Stensen, Geir Villy Isaksen, Rasmus Karstad, Hannelore Daniel, Johan SvensonAbstract:The present study assesses the permeation of cationic antimicrobial di- and tripeptides derived from Lactoferricin via interaction with the human intestinal peptide transporter hPEPT1 and via passive routes. While some tested peptides displayed moderate affinity (0.6 and 2.7 mM) for interaction with hPEPT1, none served as substrate for hPEPT1 expressed by Xenopus laevis oocytes. It is shown that structural strategies employed to generate sufficient biological activity and metabolic stability such as introduction of large hydrophobic unnatural amino acids and different C-terminal modifications counteracted hPEPT1 mediated uptake. Most of the included peptides were nevertheless shown to permeate at rates suggesting moderate to excellent human oral absorption in the applied phospholipid vesicle-based passive permeation assay. Although the main factor governing passive permeation appears to be the hydrophobicity, peptide structure was also important and the overall permeation behavior was difficult to predict. Comparisons with a theoretical prediction model were also performed.
Håvard Jenssen - One of the best experts on this subject based on the ideXlab platform.
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Lactoferricin but not lactoferrin inhibit herpes simplex virus type 2 infection in mice
Antiviral Research, 2012Co-Authors: Andrey Shestakov, Håvard Jenssen, Inger Nordstrom, Kristina ErikssonAbstract:We have evaluated the potential of bovine lactoferrin and Lactoferricin for their ability to prevent and/or treat genital HSV-2 infection in mice. We confirm previous data showing that both lactoferrin and Lactoferricin have antiviral properties in vitro and can inhibit HSV-2 infection of GMK cells in a dose-dependent manner. When tested in vivo, Lactoferricin but not lactoferrin was also a potent inhibitor of HSV-2 infection. When admixed with virus prior to inoculation, Lactoferricin inhibited disease development and significantly reduced the viral load in a genital model of HSV-2 infection in mice. Lactoferrin and Lactoferricin were also tested for their ability to stimulate the production of chemokines. Neither of the compounds induced the production of CCL3, CCL5, CXCL1 or CXCL2 by mouse splenocytes in vitro. However, when tested in vivo, both lactoferrin and Lactoferricin were able to induce local vaginal production of CCL5. Lactoferrin also induced CXCL2 production. The prophylactic and/or therapeutic effects of lactoferrin or Lactoferricin were also tested. But none of the compounds were efficient in blocking HSV-2 infection when given 24h prior to HSV-2 infection. Lactoferricin however showed promising results as a therapeutic agent and delayed both disease onset by 3days as well as reducing the viral load almost 15-fold when given as a single dose 24h post-infection. These data show that Lactoferricin can block genital herpes infection in mice, and perhaps also be used for post-infection treatment.
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inhibition of hsv cell to cell spread by lactoferrin and Lactoferricin
Antiviral Research, 2008Co-Authors: Håvard Jenssen, Robert E. W. Hancock, Kjersti Sandvik, Jeanette Hammer Andersen, Tore Jarl GuttebergAbstract:The milk protein lactoferrin (Lf) has multiple functions, including immune stimulation and antiviral activity towards herpes simplex virus 1 and 2 (HSV-1 and HSV-2); antiviral activity has also been reported for the N-terminal pepsin-derived fragment Lactoferricin (Lfcin). The anti-HSV mode of action of Lf and Lfcin is assumed to involve, in part, their interaction with the cell surface glycosaminoglycan heparan sulfate, thereby blocking of viral entry. In this study we investigated the ability of human and bovine Lf and Lfcin to inhibit viral cell-to-cell spread as well as the involvement of cell surface glycosaminoglycans during viral cell-to-cell spread. Lf and Lfcin from both human and bovine origin, inhibited cell-to-cell spread of both HSV-1 and HSV-2. Inhibition of cell-to-cell spread by bovine Lfcin involved cell surface chondroitin sulfate. Based on transmission electron microscopy studies, human Lfcin, like bovine Lfcin, was randomly distributed intracellularly, thus differences in their antiviral activity could not be explained by differences in their distribution. In contrast, the cellular localization of iron-saturated (holo)-Lf appeared to differ from that of apo-Lf, indicating that holo- and apo-Lf may exhibit different antiviral mechanisms.
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Bovine lactoferrin and Lactoferricin interfere with intracellular trafficking of Herpes simplex virus-1.
Biochimie, 2008Co-Authors: Alexandra K. Marr, M. Roshan Moniri, Håvard Jenssen, Robert E. W. Hancock, Nelly PantéAbstract:Although both lactoferrin (Lf), a component of the innate immune system of living organisms, and its N-terminal pepsin cleavage product Lactoferricin (Lfcin) have anti-herpes activity, the precise mechanisms by which Lf and Lfcin bring about inhibition of herpes infections are not fully understood. In the present study, experiments were carried out to characterize the activity of bovine Lf and Lfcin (BLf and BLfcin) against the Herpes simplex virus-1 (HSV-1). HSV-1 cellular uptake and intracellular trafficking were studied by immunofluorescence microscopy. In comparison to the untreated infected control cells, both the BLf- and BLfcin-treated cells showed a significant reduction in HSV-1 cellular uptake. The few virus particles that were internalized appeared to have a delayed intracellular trafficking. Thus, in addition to their interference with the uptake of the virus into host cells, Lf and Lfcin also exert their antiviral effect intracellularly.
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the anti papillomavirus activity of human and bovine Lactoferricin
Antiviral Research, 2007Co-Authors: Nitesh Mistry, Håvard Jenssen, Peter Drobni, Jonas Naslund, Vivekananda Gupta Sunkari, Magnus EvanderAbstract:Human papillomavirus (HPV) cause common warts, laryngeal papilloma and genital condylomata and is necessary for the development of cervical cancer. We have previously found that lactoferrin has antiviral activity against HPV-16 and others have demonstrated that Lactoferricin, an N-terminal fragment of lactoferrin, has inhibitory activities against several viruses. Two cell lines and two virus types, HPV-5 and HPV-16, were used to study if lactoferrin and Lactoferricin could inhibit HPV pseudovirus (PsV) infection. We demonstrated that bovine lactoferrin (bLf) and human lactoferrin (hLf) were both potent inhibitors of HPV-5 and -16 PsV infections. Among the four Lactoferricin derivatives we analyzed, a 15 amino acid peptide from bovine Lactoferricin (bLfcin) 17-31 was the most potent inhibitor of both HPV-5 and HPV-16 PsV infection. Among the other derivatives, the human Lactoferricin (hLfcin) 1-49 showed some antiviral activity against HPV PsV infection while bLfcin 17-42 inhibited only HPV-5 PsV infection in one of the cell lines. When we studied initial attachment of HPV-16, only bLfcin 17-42 and hLfcin 1-49 had an antiviral effect. This is the first time that Lactoferricin was demonstrated to have an inhibitory effect on HPV infection and the antiviral activity differed depending on size, charge and structures of the Lactoferricin.
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anti herpes simplex virus activity of lactoferrin Lactoferricin an example of antiviral activity of antimicrobial protein peptide
Cellular and Molecular Life Sciences, 2005Co-Authors: Håvard JenssenAbstract:One of the most common viral infections in humans is caused by the herpes simplex virus (HSV). It was first effectively treated in the 1970s with the introduction of acyclovir, which is still the most commonly used treatment. Naturally occurring antimicrobial proteins and peptides have also been shown to possess antiviral activity against HSV. This review will focus on the anti-HSV activity of one such protein, lactoferrin, and a small peptide fragment from its N-terminal domain, Lactoferricin. Both components have been shown to effectively block entry of HSV into the host cell. In addition to blocking HSV entry, the peptides appear to have immune stimulatory activity, although this is still somewhat controversial. Mode of action studies and knowledge about the anti-HSV activity of Lactoferricin have also been successfully employed in the design of new, more specific HSV blockers.
